Fibrosis Stages F4 Research Articles

Diagnostic performance of Mac-2 binding protein glycosylation isomer (M2BPGi) in screening liver fibrosis in health checkups.

BackgroundMild‐to‐moderate fibrosis is rarely diagnosed because the disease is asymptomatic in the early stage. The serum level of Mac‐2 binding protein glycosylation isomer (M2BPGi) has been found to increase with the severity of liver fibrosis. The aim of this study was to determine the diagnostic performance of M2BPGi in screening liver fibrosis using magnetic resonance elastography (MRE) as a reference standard and to compare it with using the aspartate aminotransferase‐to‐platelet ratio (APRI) and the Fibrosis‐4 index (FIB‐4) in health checkups.MethodsThis cross‐sectional study consecutively selected subjects at health examinations who underwent MRE and M2BPGi testing at eight health promotion centers in Korea between January and September 2019. The serum M2BPGi level was measured using the chemiluminescence enzyme immunoassay method. The measured levels were indexed using the cutoff index (COI). COI values of M2BPGi were compared with the MRE results.ResultsThe median (interquartile) values of COI for fibrosis stages F0 (normal liver stiffness), F1 (mild fibrosis), F2 (significant fibrosis), and ≥F3 (advanced fibrosis) were 0.49 (0.34‐0.61), 0.48 (0.38‐0.68), 0.64 (0.43‐1.03), and 1.01 (0.75‐1.77), respectively (P < .0001). The AUCs of the COI for the screening of fibrosis stage ≥F1, ≥F2, and ≥F3 were 0.591, 0.698, and 0.853, respectively. Using a threshold of 0.75 for COI to exclude advanced fibrosis had a sensitivity, specificity, and negative predictive value of 80.0%, 77.9%, and 98.9%, respectively. The AUC for excluding advanced fibrosis was better for M2BPGi than for FIB‐4 and APRI.ConclusionSerum M2BPGi was useful for screening significant and advanced fibrosis in health checkups.

The economic cost and health burden of non-alcoholic steatohepatitis in the EU5 countries

People with advanced liver fibrosis due to non-alcoholic steatohepatitis (NASH) (fibrosis stages F3 – F4) have a high risk of rapid progression to end-stage liver disease (ESLD). This study estimates the prevalence of NASH and the socioeconomic burden associated with its treatment in the EU5 countries (France, Germany, Italy, Spain and UK) during 2018. The socioeconomic burden of NASH per country was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH, and the economic and wellbeing costs attributable to diagnosed NASH in a base period (2018).

Metavir Fibrosis Stage in Hepatitis C–Related Hepatocellular Carcinoma and Association with Noninvasive Liver Reserve Models

BackgroundHepatitis C virus (HCV) infection is the major etiology for cirrhosis and hepatocellular carcinoma (HCC). The severity of liver fibrosis is a crucial factor in prognostic prediction. We aimed to evaluate the prognostic role of Metavir fibrosis stage in HCV-related HCC and its association with noninvasive liver reserve models. MethodsBetween 2004 and 2016, 172 patients with HCV-related HCC undergoing surgical resection were enrolled. Multivariate Cox proportional hazards model was used to identify prognostic predictors. The area under receiver operating curve (AUROC) was used for comparison in predicting cirrhosis among different noninvasive liver reserve models. ResultsIn the multivariate Cox analysis, AST > 45 IU/mL, multiple tumors, tumor size greater than 3 cm, and serum AFP > 20 ng/mL were independent risk factors linked with tumor recurrence. There was no significant association between Metavir fibrosis stage/ inflammatory activity and tumor recurrence. In the Cox model, Child-Turcotte-Pugh class B, tumor size greater than 3 cm, and Metavir fibrosis stage F3-F4 were independent predictors associated with decreased survival (all p < 0.001). In subgroup analysis, survival differences were consistently observed between patients with fibrosis stage F0–F2 and F3–F4 (p < 0.05) in either small (≤ 3 cm) or large (> 3 cm) HCC group. Among the noninvasive models, FIB-4 had the highest predictive accuracy (AUROC = 0.768, p < 0.001) to indicate cirrhosis compared to other models. ConclusionsMetavir fibrosis stage can predict survival in HCV-related HCC patients independent of tumor size. FIB-4 is the best noninvasive model to predict cirrhosis in these patients.

Serum visfatin level as a noninvasive marker for nonalcoholic fatty liver disease in children and adolescents with obesity: relation to transient elastography with controlled attenuation parameter.

Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Visfatin is an adipokine produced by visceral fat tissue and liver cells. Transient elastography with controlled attenuation parameter (CAP) noninvasively assesses liver fibrosis and steatosis. To measure visfatin level in 80 children and adolescents with obesity as a potential biomarker for NAFLD and assess its relation to transient elastography. Abdominal ultrasound, liver stiffness and CAP measurements were performed for all patients. Fasting lipid profile, fasting blood glucose, insulin level, liver and kidney functions, coagulation profile and serum visfatin levels were assessed. Among patients with obesity, 31 (38.8%) had NAFLD and 16 (20%) patients had elevated alanine aminotransferase (ALT), while 9 (11.2%) had both NAFLD and elevated ALT. Transient elastography showed that 12.5% had fibrosis stage F1, 2.5% had F2 and another 2.5% had F3 while none had F4. Using CAP, 23.8, 13.8 and 17.5% had S1, S2 and S3, respectively. Serum visfatin levels were significantly elevated in all patients compared with nonobese controls. Higher visfatin levels were found among patients with dyslipidemia, NAFLD, elevated ALT and steatosis defined by CAP. Serum visfatin was related to the degree of fibrosis and steatosis. Visfatin cutoff value 18 ng/mL could significantly detect the presence of NAFLD with 83.9% sensitivity and 81.4% specificity. Serum visfatin was positively correlated to BMI, waist circumference, waist/hip ratio, ALT, total cholesterol, liver stiffness and CAP. Visfatin could be a promising serum biomarker for monitoring liver disease among pediatric patients with obesity.

Economic and Clinical Burden of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes in the U.S.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NASH have increased risk for adverse clinical outcomes, leading to higher risk for mortality and morbidity. We built a Markov model with 1-year cycles and 20-year horizon to estimate the economic burden of NASH with T2DM in the U.S. Cohort size was determined by population size, prevalence of T2DM, and prevalence and incidence of NASH in 2017. The model includes 10 health states-NAFL, NASH fibrosis stages F0 through F3, compensated and decompensated cirrhosis, hepatocellular carcinoma, 1 year post-liver transplant, and post-liver transplant-as well as liver-related, cardiovascular, and background mortality. Transition probabilities were calculated from meta-analyses and literature. Annual costs for NASH and T2DM were taken from literature and billing codes. We estimated that there were 18.2 million people in the U.S. living with T2DM and NAFLD, of which 6.4 million had NASH. Twenty-year costs for NAFLD in these patients were $55.8 billion. Over the next 20 years, NASH with T2DM will account for 65,000 transplants, 1.37 million cardiovascular-related deaths, and 812,000 liver-related deaths. This model predicts significant clinical and economic burden due to NASH with T2DM over the next 20 years. In fact, this burden may be greater since we assumed conservative inputs for our model and did not increase costs or the incidence of T2DM over time. It is highly likely that interventions reducing morbidity and mortality in NASH patients with T2DM could potentially reduce this projected clinical and economic burden.

MRI cine-tagging of cardiac-induced motion for noninvasive staging of liver fibrosis.

MR elastography is a noninvasive technique that provides high diagnostic accuracy for the staging of liver fibrosis; however, it requires external hardware and mainly assesses the right lobe. To evaluate the diagnostic performance of MRI cine-tagging for staging fibrosis in the left liver lobe, using biopsy as the reference standard. Institutional Review Board (IRB)-approved two-center prospective study. Seventy-six patients with chronic liver disease who underwent an MRI cine-tagging examination and a liver biopsy within a 6-week interval. 2D-GRE multislice sequence at 3.0T with spatial modulation of the magnetization preparation sequence and peripheral pulse-wave triggering on two coronal slices chosen underneath the heart apex to capture maximal deformation with consecutive breath-holds adapted to patient cardiac frequency. A region of interest was selected in the liver close to the heart apex. Maximal strain was evaluated with the harmonic phase (HARP) technique. Spearman's correlation, Kruskal-Wallis test, Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were performed. Liver strain measured on tagged images decreased with higher histological fibrosis stage (ρ = -0.68, P < 0.0001). Strain values were significantly different between all fibrosis stages (P < 0.0001), and between groups of fibrosis stages ≤F3 vs. F4 (P < 0.05). Areas under the ROC curves were 0.95 (95% confidence interval: 0.89-1.00) to distinguish fibrosis stages F0 vs. F4, 0.81 (0.70-0.92) for stages F0 vs. ≥F1, 0.84 (0.76-0.93) for stages ≤F1 vs. ≥F2, 0.86 (0.78-0.94) for stages ≤F2 vs. ≥F3, and 0.87 (0.77-0.96) for stages ≤F3 vs. F4. MRI cine-tagging is a promising technique for measuring liver strain without additional elastography hardware. It could be used to assess the left liver lobe as a complement to current techniques assessing the right lobe. 1 Technical Efficacy: 3 J. Magn. Reson. Imaging 2020;51:1570-1580.

1020 The Effect of Metabolic Syndrome Components on Liver Stiffness Measurement Values After HCV Eradication

INTRODUCTION: The availability of noninvasive fibrosis measures coupled with high sustained viral response (SVR) rates has shifted the paradigm in the management of HCV infection in the direct-acting antiviral (DAA) era. Although these noninvasive tests are valuable in evaluating hepatic fibrosis prior to HCV therapy, use of these measures in monitoring fibrosis regression after HCV eradication is currently limited. There is evidence that patients who achieve SVR after therapy have a reduced risk of liver-related complications.1 This is likely attributed to the regression of fibrosis after HCV eradication.2 Other comorbidities, such as obesity, nonalcoholic steatohepatitis and diabetes mellitus may also contribute to liver-related complications.3-4 The aim of this study is to evaluate the effect of metabolic syndrome components on liver stiffness measurement (LSM) after HCV eradication. METHODS: A retrospective study of 65 HCV monoinfected patients who received DAA and achieved SVR located in a safety net hospital in Cleveland. All Patients had pretreatment LSM of more than 7k Pa. Patient’s with Fibrosis stage F4 had CP class A. Fibrosis was evaluate within 12 months before treatment and 12-24 months after SVR using Transient Elastography. Other collected parameters included BMI, history of DM, HLD and HTN, HbA1c, LDL, HDL and TGs. Demographics and hepatitis C genotype (GT) were also collected. Statistical analysis was performed using descriptive analysis, Anova, Univariate regression and Multivariate regression to compare variables for statistical significance. RESULTS: Among all subjects (n = 65). 64.6% were male. 61.5% had Genotype 1a, 26.2% had genotype 1b and 6.2% had genotype 2. 33.8% were diabetic, 64.6% had hyperlipidemia, and 66.2% patients had hypertension. The mean pre-treatment LSM was 14.4kPa (SD 10.0) and the mean post-treatment LSM was 9.33 kPa (SD 5.3). The mean of delta-stiffness was 5.1 kPa (SD 9.7). 53.8% patients dropped their LSM by 3 kPa or more after SVR. In univariate logistic regression, age (P = 0.675), race (P = 0.11), genotype (P = 0.688), BMI (P = 0.709), diabetes (P = 0.661), hyperlipidemia (P = 0.743), and hypertension (P = 0.545) failed to show any significant correlation with significant drop (≥3kPa) in liver stiffness measurement. CONCLUSION: Sustained viral response after direct-acting antiviral (DAA) therapy leads to significant improvement in LSM within 48 months of therapy completion. Metabolic syndrome components has no significant effect on LSM improvement after SVR.

2966 A Sub-Analysis of Puerto Rican Hepatitis C Infected Patients Enrolled in the Phase 2 and 3 Glecaprevir-Pibrentasvir Clinical Program

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and advanced liver disease, and viral clearance is associated with reduced risk of developing cirrhosis, hepatic decompensation, and death. Glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) are direct-acting antivirals (DAAs) co-formulated as a once-daily, fixed-dose combination regimen (G/P) to treat genotype (GT) 1‒6 HCV infection. G/P has been licensed in the United States and Europe, supported by a phase 2/3 global clinical trial program demonstrating high efficacy with a favorable safety profile. The objective of this study was to describe the clinical characteristics and virologic response to G/P in Puerto Rican (PR) patients included in the G/P clinical program. METHODS: Data were pooled from 14 phase 2, 3, and 3b clinical trials conducted in 32 countries and representing 3,233 treatment-naive and treatment-experienced patients with chronic HCV GT1–6 infection who received G/P once-daily for 8, 12, or 16 weeks. The primary endpoints were percentage of patients with sustained virologic response 12 weeks after treatment (SVR12) and percentage with treatment-emergent adverse events (AEs). RESULTS: From the 3,233 patients included in the G/P clinical program, this sub-analysis included 79 (2%) patients from sites in Puerto Rico. Overall, 52 (66%) were male, 64 (81%) were white race and the median age was 56 years (range: 29–78). Most patients were infected with HCV GT1 (n = 69; 87%), of whom 71% (49/69) had GT1a infection, and overall, 63 (80%) were treatment-naïve. Additionally, 39 (53%) patients had baseline fibrosis stage F0–F1, while 25 (34%) had stage F4. The overall SVR12 rate was 97.5% (77/79), with two patients not achieving SVR12 due to non-virologic reasons (both missing SVR12 data). AEs occurred in 38 (48%) patients, with none leading to discontinuation. Serious AEs occurred in 4 (5%) patients but none were deemed by investigators to be related to DAAs. There were 4 (5%) grade ≥3 laboratory abnormalities, and none were deemed clinically meaningful. CONCLUSION: G/P achieved high SVR12 rates and was well-tolerated in Puerto Rican patients enrolled in the G/P clinical trial program. The efficacy and safety profile of G/P in Puerto Rican patients was comparable to the overall patient population in the G/P registrational trial program, and SVR12 rates were comparable to real-world studies of G/P.

Validation of Novel Fibrosis Index (NFI) for assessment of liver fibrosis: comparison with transient elastography (FibroScan)

BackgroundIn this study, we collated cheap and readily available non-invasive biomarkers and FibroScan score in predicting fibrosis stages in chronic hepatitis C virus (HCV) infection.MethodsWe studied 1898 patients with HCV...

Deriving the optimal limit of detection for an HCV point-of-care test for viraemic infection: Analysis of a global dataset

Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed. We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates. The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4-1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18-30 vs. 51-64 years (odds ratios [OR] 2.56; 95% CI 2.19-2.99), female vs. male sex (OR 1.32; 95% CI 1.18-1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21-1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%. In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries. We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries.

Patients With Signs of Advanced Liver Disease and Clinically Significant Portal Hypertension Do Not Necessarily Have Cirrhosis

Patients with hepatic venous pressure gradients (HVPGs) of 10 mm Hg or greater and chronic liver disease often are assumed to have cirrhosis. We investigated the association between HVPGs and cirrhosis, using histologic findings as the reference standard. We also assessed the prevalence and characteristics of patients with HVPGs of 10 mm Hg or greater without cirrhosis. We performed a retrospective analysis of 157 consecutive patients, 89 with suspected cirrhosis and hepatic hemodynamic data collected from 2015 through 2017. Biopsy specimens collected had 10 or more portal tracts from each patient and were analyzed for features of cirrhosis. Biopsy specimens with histologic features of cirrhosis were excluded and the remaining biopsy specimens were re-reviewed by an expert pathologist. The fibrosis area was calculated digitally by image analysis. HVPG identified patients with cirrhosis with an area under the receiver operating characteristic curve of 0.879: 14 of 89 patients with HVPG of 10 mm Hg or greater (16%) had no histologic features of cirrhosis (METAVIR scores <4 and Ishak scores <6). The median HVPG was 11 mm Hg (range, 10-22 mm Hg). Based on METAVIR scores, 7 patients had fibrosis stage F3, 4 patients had fibrosis stage F2, and 3 patients had fibrosis stages F0 or F1. The mean area of fibrosis in livers was 16.2% ± 6.5%. All 14 patients had perisinusoidal fibrosis and 8 patients had hepatocyte ballooning. The most common diagnoses were nonalcoholic steatohepatitis (n= 5) and nodular regenerative hyperplasia (n= 4). An HVPG cut-off value of 12 mm Hg identified patients with cirrhosis with 92% specificity, misclassifying 5 patients with different etiologies of liver disease. In a retrospective analysis of 89 consecutive patients with chronic liver disease and an HVPG of 10 mm Hg or greater, 16% were not found to have cirrhosis upon biopsy analysis. Most of these patients had nonalcoholic steatohepatitis or nodular regenerative hyperplasia. Perisinusoidal fibrosis and hepatocyte ballooning might increase sinusoidal pressure. An HVPG cut-off value of 12 mm Hg or greater identified patients with cirrhosis with 92% specificity.

Insulin resistance does not impair response of chronic hepatitis C virus to direct-acting antivirals, and improves with the treatment

Insulin resistance (IR) is a common complication in chronic hepatitis C virus (HCV) patients. The impact of IR on outcome of therapy with direct antivirals has not been studied. The aim was to assess the impact of direct-acting antiviral (DAA) therapy on IR status in chronic HCV patients. A total of 511 patients [mean age: 50.7±10.4 years, 29.7% pegylated interferon and ribavirin (RBV) experienced] were enrolled. Patients with uncontrolled diabetes, decompensated liver disease, or previous nonresponse to DAAs were excluded. Homeostatic model assessment (HOMA) was calculated before and 12 weeks after treatment, and IR was defined as HOMA greater than 1.9. Patients were treated according to the treating physician's choice, and received 12 weeks of either ombitasvir/ritonavir/paritaprevir/RBV (n=28); sofosbuvir (SOF)/simeprevir (n=36); SOF/ravidasvir (n=101); SOF/pegylated interferon/RBV (n=192); or 24 weeks of SOF/RBV (n=154). Most patients received IR pretreatment (80.6%); 51.3% had fibrosis stage F4 and 24.7% had diabetes. A sustained virological response (SVR) at 12 weeks after treatment (SVR12) was achieved in 465 (91%) patients. SVR12 was achieved in 90.5% of patients with IR and in 92.9% of patients without IR (P=0.560), and pretreatment HOMA was not different in responders and nonresponders (P=0.098). The number of patients with IR decreased significantly in patients who achieved an SVR much more than in nonresponders (P<0.0001) and HOMA improved significantly more in patients with SVR than in nonresponders (P=0.001). All treatment protocols were associated with a comparable improvement in HOMA (P=0.101). Predictors of SVR12 included age, platelets, and liver stiffness, but not pretreatment IR. IR does not impair the response of patients with HCV treated with DAAs, and improves significantly in patients who achieve an SVR.

Possibilities of therapeutic correction of hyperammonemia and minimal hepatic encephalopathy in patients with chronic hepatitis C at the pre-cirrhotic stage.

Study of the social consequences of cognitive disorders in minimal hepatic encephalopathy (MHE) in patients with chronic genotype 1 hepatitis C and the possibilities of their pharmacological correction with L-ornithine-L-aspartate (LOLA, Hepa-Merz). The study group included 60 male patients diagnosed with chronic hepatitis C, genotype 1 with fibrosis stage F1 according to the METAVIR scale, and presented with MHE. The average age of the patients was 34.2±5.3 years. The control group included 20 healthy men aged 34.1±5.8 years without liver disease. Intermittent treatment with LOLA was given to the study group at 15 g once daily in the morning for 2 months with 2-month off-treatment intervals, with the total treatment duration of 12 months. In the course of treatment, MHE dynamics was assessed using the critical flicker fusion frequency (CFF) test and the number connecting test (NCT), as well as by serum concentrations of ammonium ion. The LOLA efficacy endpoint was the change in the frequency of violations of traffic rules (traffic code). A significant decrease in the concentration of ammonium ion was observed after 5 months of treatment (135.53 and 82.9 μmol/L, p=0.002) and maintained throughout the study. The results of the CFF test significantly improved by the end of the 1st month of LOLA treatment (p=0.008), remaining at the achieved level for 9 months. The NCT parameters reached their minimum values after 5 months (p&lt;0.001) and remained at this level throughout the study. During the study period, the frequency of traffic code violations by participants decreased from 60 to 40% (р=0.03). Fractional treatment with LOLA leads to a decrease in the blood concentration of ammonium ion and, consequently, to an improvement in psychometric test results and a decrease in the frequency of traffic code violations. The result achieved can have an impact on the accident rate reduction.

Improvement in hepatitis C virus patients with advanced, compensated liver disease after sustained virological response to direct acting antivirals.

The outcome of patients with chronic hepatitis C virus infection (HCV) and advanced, compensated liver disease after sustained virological response (SVR) to direct-acting antivirals (DAAs) has not yet been completely depicted. We aimed to assess the clinical, biochemical and instrumental outcome of patients with advanced, compensated chronic HCV-related liver disease with DAA-induced SVR to DAAs and who had at least 1-year follow-up. Fifty-two patients with cirrhosis (n=27) and fibrosis stage F3 (n=25) followed up for a median of 60weeks after successful DAA treatment were included. Laboratory work-up, including APRI and FIB-4 scores, liver transient elastography and measurement of the spleen bi-polar diameter were carried out before treatment and at the end of follow-up. Liver stiffness decreased (P<0.0001) from a median baseline of 15.2kPa (12.0-20.0) to 9.3kPa (7.5-12.0) at follow-up. A liver stiffness value suggestive of the presence (ie, ≥21.0kPa) of clinically significant portal hypertension was found in 13 patients (25.0%) at baseline and in seven patients (13.5%) at follow-up (P=0.037). Both APRI (P<0.0001) and FIB-4 score (P=0.025) progressively decreased, while platelet count increased (143×109 /L [117-176] to 153×109 /L [139-186], P=0.003), and spleen bi-polar diameter decreased (120mm [112-123] to 110mm [102-116], P=0.0009) from baseline to the end of follow-up. In patients advanced, compensated chronic liver disease, liver stiffness significantly improves in the long-term after SVR, and this improvement is accompanied by an amelioration of indirect indices of liver fibrosis and function, and by a decrease in parameters of portal hypertension.

Plasma microRNA: A novel non-invasive biomarker for HBV-associated liver fibrosis staging.

The aim of the present study was to evaluate the potential use of 7 plasma miRNAs for liver fibrosis staging in patients with chronic hepatitis B virus (HBV) infection. Relative levels of miRNAs were measured using quantitative polymerase chain reaction and used to develop a diagnostic panel. A receiver operating characteristic (ROC) curve was drawn to evaluate the performance of individual miRNAs and the whole panel. It was identified that hsa-miR-122 exhibited significantly different expression levels between F4 and F3, F2, F1, and F0 fibrosis stages (P<0.05), and between F2 and F1 stages (P=0.045); hsa-miR-146a-5p, hsa-miR-29c-3p and hsa-miR-223 exhibited significantly different expression levels between F4 and F0 stages. ROC analysis revealed that hsa-miR-122-5p, hsa-miR-223 and hsa-miR-29c-3p identified patients with ≥F2 fibrosis with area under the curve (AUC) =0.745, 0.631 and 0.670, respectively. hsa-miR-122-5p identified patients with ≥F3 disease (AUC=0.783). hsa-miR-122-5p, hsa-miR-223 and hsa-miR-29c-3p identified patients with cirrhosis with AUC=0.776, 0.617 and 0.619, respectively. The miRNA panel exhibited a higher accuracy compared with individual miRNAs in discriminating between ≥F2, ≥F3 and F4 fibrosis stages with AUC=0.904, 0.889 and 0.835, respectively. hsa-miR-122-5p, hsa-miR-146a, hsa-miR-29c and hsa-miR-223 were positively correlated with fibrosis stage. hsa-miR-122-5p and hsa-miR-381-3p were negatively correlated with alanine aminotransferase, aspartate transaminase and HBV viral DNA load. These 7 miRNAs may serve as potential biomarkers of liver fibrosis in patients with HBV-associated fibrosis. The miRNA panel may serve as a novel non-invasive method for liver fibrosis staging.

Understanding Patient Preferences and Unmet Needs in Non-alcoholic Steatohepatitis (NASH): Insights from a Qualitative Online Bulletin Board Study.

IntroductionThe aim of this work was to understand how patients with non-alcoholic steatohepatitis (NASH) perceive their disease, unmet needs, and expectations regarding future treatment through online bulletin board (OBB) qualitative research.MethodsOBB is an asynchronous online qualitative market research tool that provides an open forum for interactive discussion among participants. Patients with NASH were recruited via physician referral and completed a screener questionnaire to ensure their eligibility and willingness to participate. A trained moderator managed the discussion that allowed open answers and responses to other participants’ posts. Patient responses were analyzed using a combination of different qualitative analytical tools.ResultsThe OBB ran for 4 days and included 16 patients (n = 8, UK; n = 8, US) with NASH (fibrosis stages F1–F3) and comorbidities including diabetes/prediabetes (n = 9) and obesity (n = 12). The key insights were (1) patients with NASH have a poor understanding of the disease, its progression, and management—they feel a lack of adequate educational support from their physicians; (2) diagnosis of NASH is incidental in most cases, mainly because patients fail to spontaneously associate their signs or symptoms with their liver condition; (3) comorbidities (obesity and diabetes) are more concerning to patients than NASH; and (4) patients perceive that NASH impacts their social life and work performance in more advanced stages.ConclusionsThis OBB provided valuable patient insights into NASH disease perception and management and revealed unmet need areas. In light of no approved therapies, these patient insights can inform early drug development strategies and stakeholder discussions on NASH.FundingNovartis Pharma AG, Basel.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0856-0) contains supplementary material, which is available to authorized users.

Increased red cell width distribution to lymphocyte ratio is a predictor of histologic severity in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic disease that is increasingly being recognized in recent years. In this study, we sought to identify noninvasive markers of the severity of cirrhosis in patients with PBC based on routinely investigated laboratory parameters.Ninety-four patients with histologically-confirmed PBC based on liver biopsy performed between January 2013 and December 2017 at the First Hospital of Jilin University were divided into 2 groups: early-stage cirrhosis (fibrosis stage F1 and F2; n = 74) and advanced-stage cirrhosis (fibrosis stage F3 and F4; n = 20).Patients with advanced-stage had significantly higher red blood cell distribution width (RDW) (15.2 vs 13.7; P = .003) and significantly lower platelet (163.35 vs 202.73; P = .032) and lymphocyte counts (1.47 vs 1.79; P = .018) as compared with patients with early-stage cirrhosis. Advanced-stage cirrhosis was associated with significantly higher RDW to platelet ratio (RPR), RDW to lymphocyte ratio (RLR), aspartate aminotransferase to platelet ratio index (APRI), and fibrosis index based on the 4 factors (FIB-4) as compared with early-stage cirrhosis. RLR showed the highest area under receiver operating characteristic curve (AUROC) (0.744). The sensitivity and specificity of RLR were 65% and 78.3%, respectively. RLR had higher AUROC than the other 3 noninvasive markers.The noninvasive markers RPR, RLR, APRI, and FIB-4 showed good diagnostic accuracy for advanced-stage cirrhosis. These markers are easily acquired by routine laboratory tests and are reproducible predictors of the severity of PBC. RLR is a novel marker that may serve as a valuable supplement to APRI and FIB-4 for predicting the severity of cirrhosis.

Liver Stiffness Improvement Is Associated With Amelioration of Indirect Parameters of Portal Hypertension One Year After Sustained Virological Response to Direct Acting Antivirals in Chronic Hepatitis C Patients

Introduction: The outcome of patients with chronic hepatitis C virus infection (HCV) and advanced, compensated liver disease who have obtained a sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) has not yet been fully elucidated. In particular, previous studies included heterogeneous patients populations thus making difficult to draw definite conclusions on this issue. In this prospective study, our aim was to assess the clinical and instrumental outcome of patients with advanced, compensated chronic HCV-related liver disease who had obtained a SVR to DAAs treatment, and who had at least 1-year follow-up following the end of treatment. Methods: We included in this study 52 patients with cirrhosis (n=27) and a METAVIR fibrosis stage F3 (n=25) who were followed-up for a median of 60 weeks (95%CI, 52-68 weeks) following the end of successful DAAs treatment. Clinical work-up, liver transient elastography, and measurement of the spleen bi-polar diameter were carried out before treatment and at the end of follow-up. The transient elastography results compatible with the presence (≥21.0kPa) or absence (<13.6kPa) of clinically significant portal hypertension were obtained from the current literature. Results: Liver stiffness decreased (P=0.0001) from a median baseline of 15.2kPa (12.0-20.0) to 9.3kPa (7.5-12.0) at follow-up. Overall, absolute liver stiffness values decreased in 45 patients (86.6%), were unmodified in 2 patients (3.8%), and increased in 5 patients (9.6%). At the end of follow-up liver stiffness values were compatible with a METAVIR stage F4 in 17 patients (32.6%), F3 in 8 patients (15.4%), F2 in 7 patients (13.5%), F1 in 13 patients (25.0%), and F0 in 7 patients (13.5%). We observed that a liver stiffness value suggestive of the presence (≥21.0kPa) of clinically significant portal hypertension was found in 13 patients (25.0%) at baseline and in 7 patients (13.5%) at follow-up (P=0.037). Platelet count significantly increased [143x109/L (117-176) to 153 x109/L (139-186), P=0.003] and spleen bi-polar diameter significantly decreased [120mm (112-123) to 110mm (102-116), P=0.0009] from baseline to the end of follow-up. Conclusion: Conclusions: In patients advanced, compensated chronic liver disease, liver stiffness significantly improves in the long-term after SVR, and this improvement is accompanied by an amelioration of indirect indices of portal hypertension.

Dynamic Changes of the Aspartate Aminotransferase-to-Platelet Ratio and Transient Elastography in Predicting a Histologic Response in Patients With Chronic Hepatitis B After Entecavir Treatment.

To evaluate the dynamic changes of the aspartate aminotransferase (AST)-to-platelet ratio and transient elastography (FibroScan; Echosens, Paris, France) in predicting a histologic response in patients with chronic hepatitis B (CHB) after entecavir treatment. A total of 148 patients with CHB were enrolled. Patient information was collected. All patients received liver biopsy and FibroScan before and after 96 weeks of entecavir treatment. Baseline liver biopsy results showed that there were 7 patients without liver fibrosis (fibrosis stage F0; 4.7%), 51 patients with mild liver fibrosis (F1; 34.5%), and 90 patients with advanced liver fibrosis (>F1; 60.9%). The liver stiffness value and AST-to-platelet ratio increased significantly as the METAVIR score of the patients increased from F0 to F4 (P < .001). After antiviral therapy for 96 weeks, the average liver stiffness value measured by FibroScan and the AST-to-platelet ratio showed a significant decrease. When we use a decreased liver stiffness value to predict a histologic response, the area under the receiver operating characteristic curve was 0.70 (95% confidence interval, 0.61-0.79; P < .001), and the sensitivity and specificity were 74.3% and 68.8%, respectively. The decrease of the AST-to-platelet ratio also could predict the histologic response of patients with CHB; the area under the receiver operating characteristic curve was 0.77 (95% confidence interval, 0.69-0.86; P < .001) with sensitivity of 76.2% and specificity of 70.2%. A multivariate analysis indicated that a high hepatitis B virus DNA viral load (odds ratio, 1.44; P = .04) and high METAVIR score (odds ratio, 1.38; P = .02) were independent risk factors for the histologic response. Both the AST-to-platelet ratio and FibroScan value can effectively predict a histologic response in patients with CHB during entecavir treatment. Therefore, they can be used to monitor these patients during antiviral treatment to avoid multiple liver biopsies.

Feasibility and Efficacy of Transient Elastography using the XL probe to diagnose liver fibrosis and cirrhosis: A meta-analysis.

Background:Transient elastography (TE) has been validated as an effective noninvasive tool for the assessment of liver fibrosis. The XL probe is a new probe that was initially designed for use in patients with obesity. A meta-analysis was performed to assess the feasibility and efficacy of TE using the XL probe.Methods:In September 2016, we systematically searched the PubMed and Science Direct search engines. The feasibility of TE was evaluated based on the failure rate and the results of the unreliable liver stiffness measurement (LSM). The efficacy of TE was measured using sensitivity, specificity, and summary receiver-operating characteristic as measures/indices assessed in different stages of fibrosis. Heterogeneity was measured using the chi-squared test and the Q-statistic. We used the 95% confidence interval (95% CI) as an effect measure.Results:We included 8 studies in the meta-analysis. When the XL was compared to the M probe, the former showed a lower risk of failure rate [relative risk (RR) 0.24, 95% CI 0.14–0.38]. In patients with a body mass index ≥30 kg/m2, the XL probe showed a statistically significantly lower risk of failure rate (RR 0.16, 95% CI 0.08–0.32) but no significant improvement (RR 0.76, 95% CI 0.50–1.16) in the unreliable LSM result. In patients showing liver fibrosis stage ≥F2, the XL probe showed a sensitivity of 0.56 (95% CI 0.39–0.72), specificity of 0.71 (95% CI 0.61–0.79), and an area under the curve (AUC) of 0.71. The results observed in patients with liver fibrosis stage F4 were more promising with a sensitivity of 0.84 (95% CI 0.76–0.90), specificity of 0.78 (95% CI 0.70–0.84), and an AUC of 0.88.Conclusion:TE using the XL probe demonstrates significant diagnostic utility in patients with liver fibrosis and is likely to be more reliable than the M probe in patients with obesity. Large prospective multicenter studies are, however, necessary to establish the new cut-off values to be used for the XL probe in patients with obesity.